The main objective of this project is the development of new chemistry for preparing combinatorial libraries of biomimetics--compounds that mimic the building blocks of life such as amino acids, nucleosides, or carbohydrates. The key theme of this project will be the development of new methods for the combinatorial synthesis of scaffold-diverse libraries. In addition, the combinatorial libraries targeted within this project will incorporate pharmacophoric diversity while retaining critical drug-like features that will maximize the utility of these libraries in downstream biomedical applications. The overall goals of this project will be to (1) develop multicomponent reactions that provide for easy incorporation of peripheral diversity into biomedically important scaffolds, (2) develop methods that allow for the synthesis of diverse scaffold types within a single library, (3) emphasize control of stereochemistry and conformational diversity in library synthesis. These goals will be addressed through four specific aims, including (1) the development of a new three-component ring-expansion reaction, and (2) the investigation of a tandem Lewis acid promoted cycloaddition/intramolecular Schmidt reaction for combinatorial chemistry. In a second subproject, (3) the stereoselective synthesis of a unique class of C-5' modified nucleoside libraries and (4) the stereoselective synthesis of novel azasugar and polysubstituted piperidine libraries will be examined.